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Silveira-Freitas JEP, Campagnolo ML, dos Santos Cortez M, de Melo FF, Zarpelon-Schutz AC, Teixeira KN. Long chikungunya? An overview to immunopathology of persistent arthralgia. World J Virol 2024; 13:89985. [PMID: 38984075 PMCID: PMC11229846 DOI: 10.5501/wjv.v13.i2.89985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 02/09/2024] [Accepted: 04/12/2024] [Indexed: 06/24/2024] Open
Abstract
Chikungunya fever (CF) is caused by an arbovirus whose manifestations are extremely diverse, and it has evolved with significant severity in recent years. The clinical signs triggered by the Chikungunya virus are similar to those of other arboviruses. Generally, fever starts abruptly and reaches high levels, followed by severe polyarthralgia and myalgia, as well as an erythematous or petechial maculopapular rash, varying in severity and extent. Around 40% to 60% of affected individuals report persistent arthralgia, which can last from months to years. The symptoms of CF mainly represent the tissue tropism of the virus rather than the immunopathogenesis triggered by the host's immune system. The main mechanisms associated with arthralgia have been linked to an increase in T helper type 17 cells and a consequent increase in receptor activator of nuclear factor kappa-Β ligand and bone resorption. This review suggests that persistent arthralgia results from the presence of viral antigens post-infection and the constant activation of signaling lymphocytic activation molecule family member 7 in synovial macrophages, leading to local infiltration of CD4+ T cells, which sustains the inflammatory process in the joints through the secretion of pro-inflammatory cytokines. The term "long chikungunya" was used in this review to refer to persistent arthralgia since, due to its manifestation over long periods after the end of the viral infection, this clinical condition seems to be characterized more as a sequel than as a symptom, given that there is no active infection involved.
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Affiliation(s)
| | | | | | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Campus Anísio Teixeira, Vitória da Conquista, Bahia 45029-094, Brazil
| | - Ana Carla Zarpelon-Schutz
- Campus Toledo, Universidade Federal do Paraná, Toledo, Paraná 85919-899, Brazil
- Programa de Pós-graduação em Biotecnologia, Palotina, Universidade Federal do Paraná-Setor Palotina, Paraná 85950-000, Brazil
| | - Kádima Nayara Teixeira
- Campus Toledo, Universidade Federal do Paraná, Toledo, Paraná 85919-899, Brazil
- Programa Multicêntrico de Pós-graduação em Bioquímica e Biologia Molecular, Palotina, Universidade Federal do Paraná-Setor Palotina, Paraná 85950-000, Brazil
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Ju HJ, Bae JM. Bridging Molecular Mechanism and Clinical Practice in Vitiligo Treatment: An Updated Review. Dermatology 2024; 240:474-486. [PMID: 38417409 DOI: 10.1159/000537810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 02/11/2024] [Indexed: 03/01/2024] Open
Abstract
BACKGROUND Treatment of vitiligo seeks to achieve three goals: cessation of disease progression, regeneration of pigmentation, and prevention of recurrence. SUMMARY Number of nonsurgical interventions are available that suppress the autoimmune response and regenerate the melanocytes from the reservoir: phototherapy including psoralen and ultraviolet A, narrowband ultraviolet B, and 308-nm excimer and 311-nm Titanium:Sapphire lasers; topical agents including topical calcineurin inhibitors, topical corticosteroids, and topical 5-fluorouracil; and systemic agents including corticosteorids, mycophenolate mofetil, cyclosporine, methotrexate, minocycline, afamelanotide, and antioxidants. In recent years, a great advance has been made in the understanding of pathogenesis of vitiligo, and JAK inhibitors are being investigated as a new treatment. Minimally invasive procedures such as fractional lasers or microneedling can help achieve the optimal treatment outcome when used properly. KEY MESSAGES Our review describes various treatment modalities for vitiligo based on their molecular mechanism of action. Bridging the gap between molecular mechanisms and therapeutic options would be a valuable reference for physicians in clinical practice.
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Affiliation(s)
- Hyun Jeong Ju
- Department of Dermatology, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung Min Bae
- Department of Dermatology, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Wroński J, Ciechomska M, Kuca-Warnawin E. Impact of methotrexate treatment on vaccines immunogenicity in adult rheumatological patients - Lessons learned from the COVID-19 pandemic. Biomed Pharmacother 2023; 165:115254. [PMID: 37542854 DOI: 10.1016/j.biopha.2023.115254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 08/07/2023] Open
Abstract
Despite the development of new biological and synthetic targeted therapies, methotrexate remains one of the most commonly used immunomodulatory drugs in rheumatology. However, its effect on the immunogenicity of vaccines has been studied only to a limited extent until recently, resulting in the lack of clear guidelines on the use of methotrexate during vaccination. Significant progress was made during the COVID-19 pandemic due to the dynamic development of research on vaccines, including patients with autoimmune inflammatory rheumatic diseases. In the following literature review, we present a summary of what we know so far on the impact of methotrexate on post-vaccination response in adult rheumatology patients, taking into account the lessons learned from the COVID-19 pandemic. Studies on the effect of methotrexate on the immunogenicity of influenza, pneumococcal, herpes zoster, tetanus/diphtheria/pertussis, hepatitis A, yellow fever, and COVID-19 vaccines are described in detail, including the effect of methotrexate on the humoral and cellular response of individual vaccines. The available evidence for recommendations for withholding methotrexate in the post-vaccination period is presented. Lastly, an overview of potential immunological mechanisms through which MTX modulates the immunogenicity of vaccinations is also provided.
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Affiliation(s)
- Jakub Wroński
- Department of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland.
| | - Marzena Ciechomska
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland
| | - Ewa Kuca-Warnawin
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland
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Lama M, Sarkar R, Ghosh B. Serum Cytokine Profiles in Patients with Rheumatoid Arthritis Before and After Treatment with Methotrexate. J Interferon Cytokine Res 2023; 43:344-350. [PMID: 37566477 DOI: 10.1089/jir.2023.0078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/13/2023] Open
Abstract
Rheumatoid arthritis (RA) is an inflammatory autoimmune illness affecting around 1% of the population globally. Cytokines have a crucial role in the pathogenesis of RA. The objectives of the present study were to compare the serum cytokine profiles between methotrexate (MTX)-treated and MTX-naive RA patient groups, MTX-treated RA patient group and healthy controls, and MTX-naive RA patient group and healthy controls. Enzyme linked immunosorbent assay (ELISA) kits were used to quantify the serum concentrations of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-17, IL-6, interferon-gamma (IFN-γ), and IL-10 in 80 RA patients (48 MTX treated and 32 MTX naive) and 80 healthy controls. For all cytokine assays, absorbance was measured at 450 nm using a microplate reader (Bio-Rad). Independent sample t-test was used to compare the serum cytokine concentrations between the study groups using SPSS version 25. MTX-treated RA patient group had significantly reduced serum levels of TNF-α (36.13 ± 17.64 versus 45.82 ± 23.07, *P = 0.037), IL-17 (307.85 ± 151.74 versus 435.42 ± 241.19, **P = 0.006), and IFN-γ (414.93 ± 212.13 versus 527.15 ± 269.61, *P = 0.041) compared to MTX-naive RA patients. Both MTX-treated and MTX-naive RA patient groups had significantly high serum levels of TNF-α, IL-1β, IL-17, IL-6, IFN-γ, and IL-10 when compared to healthy controls (***P < 0.001). Downregulation of the serum concentrations of certain key cytokines, viz. TNF-α, IL-17, and IFN-γ, demonstrates the anti-inflammatory effect of MTX in RA patients.
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Affiliation(s)
- Manoj Lama
- Molecular Immunology Laboratory, Department of Zoology, University of Gour Banga, Malda, India
| | - Rajat Sarkar
- Molecular Immunology Laboratory, Department of Zoology, University of Gour Banga, Malda, India
| | - Bappaditya Ghosh
- Department of Orthopaedics, Malda Medical College and Hospital, Malda, India
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Elrewiny EM, Shawky A, Mohamed SFF, Ammar AM, Mansour M, Rageh MA. Intralesional methotrexate in the treatment of localized vitiligo: A pilot study. Australas J Dermatol 2023; 64:e207-e211. [PMID: 37166107 DOI: 10.1111/ajd.14071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 04/23/2023] [Indexed: 05/12/2023]
Abstract
BACKGROUND/OBJECTIVES Vitiligo is an immune-mediated skin disorder that targets epidermal melanocytes leading to the appearance of depigmented skin patches. Different treatment modalities have been reported with varied efficacy. We tried to evaluate the safety and efficacy of intralesional methotrexate in treating localized areas of vitiligo. METHODS Thirty participants with localized patches of vitiligo were recruited. They were treated with intralesional injections of methotrexate every 2 weeks for a maximum of six sessions. At the end of the study, the degree of repigmentation was categorized into: excellent improvement (>75% repigmentation), good improvement (50%-75% repigmentation), fair improvement (25%-50% repigmentation) and poor improvement (<25% repigmentation). RESULTS We included 7 males (23.3%) and 23 females (76.7%). Their mean age was 33.6 ± 8.6 years. The duration of the disease ranged from 1 to 22 years. Four patients had a family history of vitiligo. At the end of the study, there was a highly statistically significant improvement (p < 0.001) after treatment regarding repigmentation. CONCLUSIONS This study showed that intralesional methotrexate is a safe and effective treatment option for patients with localized vitiligo lesions. Further studies on a larger scale are needed to evaluate the long-term effects of treatment and detect the ideal dose to be injected.
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Affiliation(s)
- Emad M Elrewiny
- Department of Dermatology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Ahmed Shawky
- Department of Dermatology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | | | - Amr Mohammad Ammar
- Department of Dermatology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Mofreh Mansour
- Department of Dermatology, Faculty of Medicine, Al-Azhar University, Assiut, Egypt
| | - Mahmoud A Rageh
- Department of Dermatology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
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Zhang R, Feng Y, Zhao Z, He Y, Wang D, Wang Q, Pang X, Yao Y, Li J, Sun Z. Effect of electroacupuncture on serum inflammatory cytokines in animal models with rheumatoid arthritis: A systematic review and meta-analysis. Eur J Integr Med 2022. [DOI: 10.1016/j.eujim.2022.102187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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Freeman ML, Clagett BM, Moisi D, Yeh E, Morris CD, Ryu A, Rodriguez B, Stein JH, Deeks SG, Currier JS, Hsue PY, Anthony DD, Calabrese LH, Ribaudo HJ, Lederman MM. Methotrexate Inhibits T Cell Proliferation but Not Inflammatory Cytokine Expression to Modulate Immunity in People Living With HIV. Front Immunol 2022; 13:924718. [PMID: 35967371 PMCID: PMC9374564 DOI: 10.3389/fimmu.2022.924718] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
Inflammation associated with increased risk of comorbidities persists in people living with HIV (PWH) on combination antiretroviral therapy (ART). A recent placebo-controlled trial of low-dose methotrexate (MTX) in PWH found that numbers of total CD4 and CD8 T cells decreased in the low-dose MTX arm. In this report we analyzed T cell phenotypes and additional plasma inflammatory indices in samples from the trial. We found that cycling (Ki67+) T cells lacking Bcl-2 were reduced by MTX but plasma inflammatory cytokines were largely unaffected. In a series of in vitro experiments to further investigate the mechanisms of MTX activity, we found that MTX did not inhibit effector cytokine production but inhibited T cell proliferation downstream of mTOR activation, mitochondrial function, and cell cycle entry. This inhibitory effect was reversible with folinic acid, suggesting low-dose MTX exerts anti-inflammatory effects in vivo in PWH largely by blocking T cell proliferation via dihydrofolate reductase inhibition, yet daily administration of folic acid did not rescue this effect in trial participants. Our findings identify the main mechanism of action of this widely used anti-inflammatory medicine in PWH and may provide insight into how MTX works in the setting of other inflammatory conditions.
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Affiliation(s)
- Michael L. Freeman
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University/University Hospitals, Cleveland Medical Center, Cleveland, OH, United States
| | - Brian M. Clagett
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University/University Hospitals, Cleveland Medical Center, Cleveland, OH, United States
| | - Daniela Moisi
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University/University Hospitals, Cleveland Medical Center, Cleveland, OH, United States
| | - Eunice Yeh
- Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - Charles D. Morris
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University/University Hospitals, Cleveland Medical Center, Cleveland, OH, United States
| | - Angela Ryu
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University/University Hospitals, Cleveland Medical Center, Cleveland, OH, United States
| | - Benigno Rodriguez
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University/University Hospitals, Cleveland Medical Center, Cleveland, OH, United States
| | - James H. Stein
- Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Steven G. Deeks
- Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of San Francisco School of Medicine, San Francisco, CA, United States
| | - Judith S. Currier
- Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Priscilla Y. Hsue
- Division of Cardiology, Department of Medicine, University of California, San Francisco School of Medicine, San Francisco, CA, United States
| | - Donald D. Anthony
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University/University Hospitals, Cleveland Medical Center, Cleveland, OH, United States
- Louis Stokes Cleveland Veterans Affairs Medical Center, US Department of Veterans Affairs, Cleveland, OH, United States
- Division of Rheumatic Diseases, MetroHealth Medical Center, Cleveland, OH, United States
| | - Leonard H. Calabrese
- Fasenmyer Center for Immunology, Division of Rheumatic Diseases, Cleveland Clinic, Cleveland, OH, United States
| | - Heather J. Ribaudo
- Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - Michael M. Lederman
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University/University Hospitals, Cleveland Medical Center, Cleveland, OH, United States
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Liu S, Deng Z, Chen K, Jian S, Zhou F, Yang Y, Fu Z, Xie H, Xiong J, Zhu W. Cartilage tissue engineering: From proinflammatory and anti‑inflammatory cytokines to osteoarthritis treatments (Review). Mol Med Rep 2022; 25:99. [PMID: 35088882 PMCID: PMC8809050 DOI: 10.3892/mmr.2022.12615] [Citation(s) in RCA: 91] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 12/07/2021] [Indexed: 12/17/2022] Open
Abstract
Osteoarthritis (OA), one of the most common joint diseases, is characterized by fibrosis, rhagadia, ulcers and attrition of articular cartilage due to a number of factors. The etiology of OA remains unclear, but its occurrence has been associated with age, obesity, inflammation, trauma and genetic factors. Inflammatory cytokines are crucial for the occurrence and progression of OA. The intra-articular proinflammatory and anti-inflammatory cytokines jointly maintain a dynamic balance, in accordance with the physiological metabolism of articular cartilage. However, dynamic imbalance between proinflammatory and anti-inflammatory cytokines can cause abnormal metabolism in knee articular cartilage, which leads to deformation, loss and abnormal regeneration, and ultimately destroys the normal structure of the knee joint. The ability of articular cartilage to self-repair once damaged is limited, due to its inability to obtain nutrients from blood vessels, nerves and lymphatic vessels, as well as limitations in the extracellular matrix. There are several disadvantages inherent to conventional repair methods, while cartilage tissue engineering (CTE), which combines proinflammatory and anti-inflammatory cytokines, offers a new therapeutic approach for OA. The aim of the present review was to examine the proinflammatory factors implicated in OA, including IL-1β, TNF-α, IL-6, IL-15, IL-17 and IL-18, as well as the key anti-inflammatory factors reducing OA-related articular damage, including IL-4, insulin-like growth factor and TGF-β. The predominance of proinflammatory over anti-inflammatory cytokine effects ultimately leads to the development of OA. CTE, which employs mesenchymal stem cells and scaffolding technology, may prevent OA by maintaining the homeostasis of pro- and anti-inflammatory factors.
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Affiliation(s)
- Shuyu Liu
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Zhenhan Deng
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Kang Chen
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Shengsheng Jian
- Department of Orthopedics, Luo Hu Hospital, Shenzhen, Guangdong 518001, P.R. China
| | - Feifei Zhou
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Yuan Yang
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Zicai Fu
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Huanyu Xie
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Jianyi Xiong
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Weimin Zhu
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
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Yan H, Su R, Xue H, Gao C, Li X, Wang C. Pharmacomicrobiology of Methotrexate in Rheumatoid Arthritis: Gut Microbiome as Predictor of Therapeutic Response. Front Immunol 2022; 12:789334. [PMID: 34975886 PMCID: PMC8719371 DOI: 10.3389/fimmu.2021.789334] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 12/01/2021] [Indexed: 12/12/2022] Open
Abstract
Rheumatoid arthritis (RA) is a disabling autoimmune disease with invasive arthritis as the main manifestation and synovitis as the basic pathological change, which can cause progressive destruction of articular cartilage and bone, ultimately leading to joint deformity and loss of function. Since its introduction in the 1980s and its widespread use in the treatment of RA, low-dose methotrexate (MTX) therapy has dramatically changed the course and outcome of RA treatment. The clinical use of this drug will be more rational with a better understanding of the pharmacology, anti-inflammatory mechanisms of action and adverse reaction about it. At present, the current clinical status of newly diagnosed RA is that MTX is initiated first regardless of the patients’ suitability. But up to 50% of patients could not reach adequate clinical efficacy or have severe adverse events. Prior to drug initiation, a prognostic tool for treatment response is lacking, which is thought to be the most important cause of the situation. A growing body of studies have shown that differences in microbial metagenomes (including bacterial strains, genes, enzymes, proteins and/or metabolites) in the gastrointestinal tract of RA patients may at least partially determine their bioavailability and/or subsequent response to MTX. Based on this, some researchers established a random forest model to predict whether different RA patients (with different gut microbiome) would respond to MTX. Of course, MTX, in turn, alters the gut microbiome in a dose-dependent manner. The interaction between drugs and microorganisms is called pharmacomicrobiology. Then, the concept of precision medicine has been raised. In this view, we summarize the characteristics and anti-inflammatory mechanisms of MTX and highlight the interaction between gut microbiome and MTX aiming to find the optimal treatment for patients according to individual differences and discuss the application and prospect of precision medicine.
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Affiliation(s)
- Huanhuan Yan
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Rui Su
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Hongwei Xue
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Chong Gao
- Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital/Children' s Hospital, Harvard Medical School, Boston, MA, United States
| | - Xiaofeng Li
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Caihong Wang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
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The HLA-G Immune Checkpoint Plays a Pivotal Role in the Regulation of Immune Response in Autoimmune Diseases. Int J Mol Sci 2021; 22:ijms222413348. [PMID: 34948145 PMCID: PMC8706866 DOI: 10.3390/ijms222413348] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/10/2021] [Accepted: 12/10/2021] [Indexed: 12/11/2022] Open
Abstract
The human G-leukocyte antigen (HLA-G) molecule is a non-classical major histocompatibility complex (MHC) class I molecule. The pertinence of HLA-G has been investigated in numerous studies which have sought to elucidate the relevance of HLA-G in pathologic conditions, such as autoimmune diseases, cancers, and hematologic malignancies. One of the main goals of the current research on HLA-G is to use this molecule in clinical practice, either in diagnostics or as a therapeutic target. Since HLA-G antigens are currently considered as immunomodulatory molecules that are involved in reducing inflammatory and immune responses, in this review, we decided to focus on this group of antigens as potential determinants of progression in autoimmune diseases. This article highlights what we consider as recent pivotal findings on the immunomodulatory function of HLA-G, not only to establish the role of HLA-G in the human body, but also to explain how these proteins mediate the immune response.
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11
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den Braanker H, Wervers K, Mus AMC, Bangoer PS, Davelaar N, Luime J, Tchetverikov I, Hazes JMW, Vis M, Lubberts E, Kok MR. Achieving sustained minimal disease activity with methotrexate in early interleukin 23-driven early psoriatic arthritis. RMD Open 2021; 6:rmdopen-2020-001175. [PMID: 32669451 PMCID: PMC7425114 DOI: 10.1136/rmdopen-2020-001175] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 03/13/2020] [Accepted: 04/02/2020] [Indexed: 01/14/2023] Open
Abstract
Objectives Methotrexate (MTX) is currently the recommended first-line therapy for treating psoriatic arthritis (PsA), despite lacking clear evidence. No estimates of efficacy of MTX in usual care and no clear MTX responsive clinical or laboratory variables are currently available. This study describes the response to MTX monotherapy in newly diagnosed patients with PsA in usual care. Second, we compared clinical variables and cytokine profiles in patients responding and not responding to MTX monotherapy. Methods We used data collected in the Dutch southwest Early Psoriatic Arthritis cohoRt study to select patients with PsA with oligoarthritis or polyarthritis, and at least 1 year follow-up. We analysed disease activity at 6 months of patients who started MTX monotherapy and still used MTX monotherapy 1 year after diagnosis. Cytokine profiles were determined at baseline and after 3 and 6 months with a bead-based multi-immunoassay. Results We identified 219 patients of which 183 (84%) patients started MTX monotherapy within 6 months after diagnosis. 90 patients used MTX monotherapy throughout the first year of which 44 patients (24%) reached minimal disease activity(MDA) at 6 months, decreasing to 33 patients (18%) after 1 year. Non-responders had significantly higher concentrations of interleukin (IL) 23 and IL-10 before and during MTX therapy. Conclusions Our results showed that only 18% of patients with PsA are in sustained MDA after 1 year of MTX monotherapy and non-responders more often had IL-23-driven disease. Our results indicate the need for more treat-to-target and personalised therapy strategies in PsA.
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Affiliation(s)
- Hannah den Braanker
- Department of Rheumatology and Clinical Immunology, Maasstad Hospital, Rotterdam, Netherlands.,Department of Rheumatology, Erasmus Medical Centre, Rotterdam, Netherlands
| | - Kim Wervers
- Department of Rheumatology, Erasmus Medical Centre, Rotterdam, Netherlands
| | - Adriana M C Mus
- Department of Rheumatology, Erasmus Medical Centre, Rotterdam, Netherlands
| | - Priyanka S Bangoer
- Department of Rheumatology, Erasmus Medical Centre, Rotterdam, Netherlands
| | - Nadine Davelaar
- Department of Rheumatology, Erasmus Medical Centre, Rotterdam, Netherlands
| | - Jolanda Luime
- Department of Rheumatology, Erasmus Medical Centre, Rotterdam, Netherlands
| | - Ilja Tchetverikov
- Department of Rheumatology, Albert Schweitzer Ziekenhuis, Dordrecht, Netherlands
| | - J M W Hazes
- Department of Rheumatology, Erasmus Medical Centre, Rotterdam, Netherlands
| | - Marijn Vis
- Department of Rheumatology, Erasmus Medical Centre, Rotterdam, Netherlands
| | - Erik Lubberts
- Department of Rheumatology, Erasmus Medical Centre, Rotterdam, Netherlands
| | - Marc R Kok
- Department of Rheumatology and Clinical Immunology, Maasstad Hospital, Rotterdam, Netherlands
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Guan T, Qiu Z, Su M, Yang J, Tang Y, Jiang Y, Yao D, Lai Y, Li Y, Liu C. Cardiovascular Death Risk in Primary Central Nervous System Lymphoma Patients Treated With Chemotherapy: A Registry-Based Cohort Study. Front Oncol 2021; 11:641955. [PMID: 34046345 PMCID: PMC8147725 DOI: 10.3389/fonc.2021.641955] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 04/14/2021] [Indexed: 12/24/2022] Open
Abstract
Purpose To study the cardiovascular death (CVD) risk in primary central nervous system lymphoma (PCNSL) patients with chemotherapy. Methods We obtained 2,020 PCNSL participants and 88,613 non-central nervous system lymphoma (NCNSL) participants with chemotherapy from Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2015. A 1:3 propensity score matching (PSM) was used to reduce the imbalance between PCNSL participants with and without chemotherapy, as well as the imbalance between PCNSL and NCNSL participants with chemotherapy. Competing risks regressions were conducted to evaluate the independent influence of chemotherapy on CVD. Results After 1:3 PSM, the CVD risk in PCNSL patients with chemotherapy was lower than those without chemotherapy [decreased 53%, adjusted HR, 0.469 (95% CI, 0.255–0.862; P = 0.015)] as well as NCNSL patients with chemotherapy [decreased 36%, adjusted HR in model 1, 0.636 (95% CI, 0.439–0.923; P = 0.017)]. The CVD risk of chemotherapy decreased in PCNSL patients with age at diagnosis >60 years old [adjusted HR, 0.390 (95% CI, 0.200–0.760; P = 0.006)], and those patients diagnosed at 2010 to 2015 [adjusted HR, 0.339 (95% CI, 0.118–0.970; P = 0.044)]. Conclusion PCNSL patients with chemotherapy are associated with lower CVD risk. Our findings may provide new foundations for that chemotherapy is the first-line treatment for PCNSL patients, according to a cardiovascular risk perspective.
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Affiliation(s)
- Tianwang Guan
- Department of Cardiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.,Department of Cardiology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China.,Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zicong Qiu
- Department of Cardiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.,Department of Clinical Medicine, Clinical Medical School, Guangzhou Medical University, Guangzhou, China
| | - Miao Su
- Department of Cardiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.,Department of Clinical Medicine, Clinical Medical School, Guangzhou Medical University, Guangzhou, China
| | - Jinming Yang
- Department of Cardiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.,Department of Clinical Medicine, Clinical Medical School, Guangzhou Medical University, Guangzhou, China
| | - Yongshi Tang
- Department of Clinical Medicine, Clinical Medical School, Guangzhou Medical University, Guangzhou, China
| | - Yanting Jiang
- Department of Clinical Medicine, Clinical Medical School, Guangzhou Medical University, Guangzhou, China
| | - Dunchen Yao
- Department of Oncology, Guiqian International General Hospital, Guiyang, China
| | - Yanxian Lai
- Department of Cardiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.,Department of Cardiology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
| | - Yanfang Li
- Department of Cardiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Cheng Liu
- Department of Cardiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.,Department of Cardiology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
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Mesenchymal Stem Cells Enhance Therapeutic Effect and Prevent Adverse Gastrointestinal Reaction of Methotrexate Treatment in Collagen-Induced Arthritis. Stem Cells Int 2021; 2021:8850820. [PMID: 33505476 PMCID: PMC7814936 DOI: 10.1155/2021/8850820] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 12/04/2020] [Accepted: 12/29/2020] [Indexed: 12/15/2022] Open
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by articular destruction and functional loss. Methotrexate (MTX) is effective in RA treatment. However, MTX induces several adverse events and 20%-30% of patients do not respond to MTX. Thus, it is urgent to enhance the therapeutic effects and reduce the side effects of MTX. Recent studies showed that mesenchymal stem cells (MSCs) were participants in anti-inflammation, immunoregulation, and tissue regeneration. However, whether the combined application of MSCs and MTX promotes the therapeutic effects and reduces the side effects of MTX has not been studied. In this study, we used bovine type II collagen to induce rheumatoid arthritis in mice (collagen-induced arthritis, CIA). Then, CIA mice were subjected to MTX or MSC treatment, or both. The therapeutic effect and adverse events of different treatments on RA were evaluated with micro-CT, HE staining, and immunohistochemistry in vivo. Apoptosis and proliferation of MODE-K cells were measured after treated with MTX or/and cocultured with UCs. To test M2 polarization, Raw264.7 macrophages were stimulated by MTX with different concentrations or cocultured with UCs. We found that the combined application of MSCs and MTX increased the therapeutic effects on RA, as evidenced by decreased arthritis score, inflammatory responses, and mortality. Moreover, in this combination remedy, MTX prefers to suppress inflammation by facilitating macrophage polarization to M2 type while UCs prefer to eliminate gastrointestinal side effects of MTX via mitigating the apoptosis of intestinal epithelial cells. Thus, a combination of MTX and UCs is a promising strategy for RA treatment.
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14
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ElGhareeb MI, Metwalli M, AbdelMoneim N. Combination of oral methotrexate and oral mini-pulse dexamethasone vs either agent alone in vitiligo treatment with follow up by dermoscope. Dermatol Ther 2020; 33:e13586. [PMID: 32410362 DOI: 10.1111/dth.13586] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 04/24/2020] [Accepted: 05/09/2020] [Indexed: 01/02/2023]
Abstract
This study aimed to compare the efficacy and safety of oral methotrexate (MTX) and oral mini-pulse (OMP) dexamethasone alone and in combination in the treatment of vitiligo. A total of 42 patients with vitiligo were included in the study. The patients were treated for three months and randomly assigned into three groups including 14 patients each: group A received oral MTX, group B received OMP dexamethasone, and group C received a combination of both. Follow-up was performed using digital photographs, Vitiligo European Task Force score, and dermoscopy. Disease extension significantly decreased in group C compared with that in groups A (P < .001) and B (P < .05). The frequency of intralesional pigmentation significantly increased (P < .05) in groups A and C and decreased (P < .05) in group B posttreatment noted using a dermoscope. Moreover, the frequency of micro-Koebner's phenomenon and starburst pattern significantly decreased (P < .05) in groups B and C and that of tapioca sago in group C only posttreatment.
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15
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Friedman B, Cronstein B. Mécanisme d'action du méthotrexate dans le traitement de la polyarthrite rhumatoïde. REVUE DU RHUMATISME (ED. FRANCAISE : 1993) 2020; 87:92-98. [PMID: 35068924 PMCID: PMC8782276 DOI: 10.1016/j.rhum.2020.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Le méthotrexate est utilisé dans le traitement de la polyarthrite rhumatoïde (PR) depuis les années 1980 et est souvent à ce jour le médicament de première intention pour le traitement de la PR. Dans cette revue, nous examinons plusieurs hypothèses pour expliquer le mécanisme à l'origine de l'efficacité du méthotrexate dans la PR. Celles-ci comprennent l'antagonisme du folate, la signalisation par l'adénosine, la génération d'espèces réactives de l'oxygène (ROS), la diminution des molécules d'adhérence, la modification des profils cytokiniques et l'inhibition des polyamines, entre autres. Actuellement, la signalisation par l'adénosine est probablement l'explication la plus largement acceptée du mécanisme du méthotrexate dans la PR, car le méthotrexate augmente les taux d'adénosine et suite à l'engagement de l'adénosine avec ses récepteurs extracellulaires, une cascade intracellulaire est activée et favorise un état antiinflammatoire global. Outre ces hypothèses, nous examinons le mécanisme du méthotrexate dans la PR sous l'angle de ses effets indésirables et considérons certains des nouveaux marqueurs génétiques de l'efficacité et de la toxicité du méthotrexate dans la PR. Enfin, nous discutons brièvement du mécanisme du méthotrexate en association avec un traitement de la PR par un inhibiteur du TNF-. En fin de compte, en trouvant une explication claire de la voie et du mécanisme conduisant à l'efficacité du méthotrexate dans la PR, il pourrait exister un moyen de formuler des thérapies plus puissantes avec moins d'effets secondaires.
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16
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Bedoui Y, Guillot X, Sélambarom J, Guiraud P, Giry C, Jaffar-Bandjee MC, Ralandison S, Gasque P. Methotrexate an Old Drug with New Tricks. Int J Mol Sci 2019; 20:E5023. [PMID: 31658782 PMCID: PMC6834162 DOI: 10.3390/ijms20205023] [Citation(s) in RCA: 247] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 09/16/2019] [Accepted: 09/30/2019] [Indexed: 12/16/2022] Open
Abstract
Methotrexate (MTX) is the first line drug for the treatment of a number of rheumatic and non-rheumatic disorders. It is currently used as an anchor disease, modifying anti-rheumatic drug in the treatment of rheumatoid arthritis (RA). Despite the development of numerous new targeted therapies, MTX remains the backbone of RA therapy due to its potent efficacy and tolerability. There has been also a growing interest in the use of MTX in the treatment of chronic viral mediated arthritis. Many viruses-including old world alphaviruses, Parvovirus B19, hepatitis B/C virus, and human immunodeficiency virus-have been associated with arthritogenic diseases and reminiscent of RA. MTX may provide benefits although with the potential risk of attenuating patients' immune surveillance capacities. In this review, we describe the emerging mechanisms of action of MTX as an anti-inflammatory drug and complementing its well-established immunomodulatory activity. The mechanisms involve adenosine signaling modulation, alteration of cytokine networks, generation of reactive oxygen species and HMGB1 alarmin suppression. We also provide a comprehensive understanding of the mechanisms of MTX toxic effects. Lastly, we discussed the efficacy, as well as the safety, of MTX used in the management of viral-related rheumatic syndromes.
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Affiliation(s)
- Yosra Bedoui
- Unité Mixte de Recherche Processus Infectieux en Milieu Insulaire Tropical (PIMIT), INSERM U1187, CNRS 9192, IRD 249, Université de La Réunion-Plateforme Technologique CYROI-2, rue Maxime Rivière, 97490 Sainte-Clotilde, France.
| | - Xavier Guillot
- Service de Rhumatologie, CHU La Réunion site Félix Guyon, Allée des Topazes, CS11021, 97400 Saint Denis de La Réunion, France.
| | - Jimmy Sélambarom
- Unité Mixte de Recherche Processus Infectieux en Milieu Insulaire Tropical (PIMIT), INSERM U1187, CNRS 9192, IRD 249, Université de La Réunion-Plateforme Technologique CYROI-2, rue Maxime Rivière, 97490 Sainte-Clotilde, France.
| | - Pascale Guiraud
- Unité Mixte de Recherche Processus Infectieux en Milieu Insulaire Tropical (PIMIT), INSERM U1187, CNRS 9192, IRD 249, Université de La Réunion-Plateforme Technologique CYROI-2, rue Maxime Rivière, 97490 Sainte-Clotilde, France.
| | - Claude Giry
- Laboratoire de biologie, CNR associé des arbovirus, CHU La Réunion site Félix Guyon, Allée des Topazes, CS11021, 97400 Saint Denis de La Réunion, France.
| | - Marie Christine Jaffar-Bandjee
- Laboratoire de biologie, CNR associé des arbovirus, CHU La Réunion site Félix Guyon, Allée des Topazes, CS11021, 97400 Saint Denis de La Réunion, France.
| | - Stéphane Ralandison
- Service de Rhumatologie-Médecine Interne, CHU Morafeno, Route d'Ivoloina 501, Toamasina, Madagascar.
| | - Philippe Gasque
- Unité Mixte de Recherche Processus Infectieux en Milieu Insulaire Tropical (PIMIT), INSERM U1187, CNRS 9192, IRD 249, Université de La Réunion-Plateforme Technologique CYROI-2, rue Maxime Rivière, 97490 Sainte-Clotilde, France.
- Pôle de Biologie, secteur Laboratoire d'Immunologie Clinique et Expérimentale de la zone de l'Océan Indien (LICE-OI), CHU La Réunion site Félix Guyon, Allée des Topazes, CS11021, 97400 Saint Denis de La Réunion, France.
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17
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Rheumatic manifestations of chikungunya: emerging concepts and interventions. Nat Rev Rheumatol 2019; 15:597-611. [DOI: 10.1038/s41584-019-0276-9] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2019] [Indexed: 12/15/2022]
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Abdelmaksoud A, Dave DD, Lotti T, Vestita M. Topical methotrexate 1% gel for treatment of vitiligo: A case report and review of the literature. Dermatol Ther 2019; 32:e13013. [PMID: 31265164 DOI: 10.1111/dth.13013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 06/18/2019] [Accepted: 06/27/2019] [Indexed: 01/02/2023]
Abstract
Vitiligo is quite a common hypopigmentary disorder, which may affect both children and adults with important psychological effects due to the well-known leopard skin-like appearance. Even if asymptomatic and not life threatening, vitiligo has to be increasingly studied and treated. Hitherto, the efficacy of topical methotrexate in treatment of vitiligo has not been reported. We herein reporting our preliminary observation on the promising efficacy of topical methotrexate in one patient with stable vitiligo. The patient applied topical methotrexate 1% gel twice daily for 12 weeks. Significant improvement of the lesion with no local or systemic side effects were noted during the course of therapy. We propose that this well-tolerated drug can be used for vitiligo therapy; however, further investigations should be performed to ascertain the exact topically effective dose.
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Affiliation(s)
- Ayman Abdelmaksoud
- Mansoura Dermatology, Venerology and Leprology Hospital, Mansoura, Egypt
| | | | | | - Michelangelo Vestita
- Unit of Plastic and Reconstructive Surgery, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.,Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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19
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Hambardzumyan K, Bolce RJ, Wallman JK, van Vollenhoven RF, Saevarsdottir S. Serum Biomarkers for Prediction of Response to Methotrexate Monotherapy in Early Rheumatoid Arthritis: Results from the SWEFOT Trial. J Rheumatol 2019; 46:555-563. [PMID: 30709958 DOI: 10.3899/jrheum.180537] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/09/2018] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To investigate baseline levels of 12 serum biomarkers that constitute a multibiomarker disease activity test, as predictors of response to methotrexate (MTX) in patients with early rheumatoid arthritis (eRA). METHODS In 298 patients from the Swedish Pharmacotherapy (SWEFOT) clinical trial, baseline serum levels of 12 proteins were analyzed for association with disease activity based on the 28-joint count Disease Activity Score (DAS28) after 3 months of MTX monotherapy using uni-/multivariate logistic regression. Primary outcome was low disease activity (LDA; DAS28 ≤ 3.2). RESULTS Of 298 patients, 104 achieved LDA after 3 months on MTX. Four of the 12 biomarkers [C-reactive protein (CRP), leptin, tumor necrosis factor receptor I (TNF-RI), and vascular cell adhesion molecule 1 (VCAM-1)] significantly predicted LDA based on stepwise logistic regression analysis. Dichotomization of patients using receiver-operating characteristic curve analysis-based cutoffs for these biomarkers showed significantly higher proportions with LDA among patients with lower versus higher levels of CRP or leptin (40% vs 23%, p = 0.004, and 40% vs 25%, p = 0.011, respectively), as well as among those with higher versus lower levels of TNF-RI or VCAM-1 (43% vs 27%, p = 0.004, and 41% vs 25%, p = 0.004, respectively). Combined score based on these biomarkers, adjusted for known predictors of LDA (smoking, sex, and age), associated with decreased chance of LDA (adjusted OR 0.45, 95% CI 0.32-0.62). CONCLUSION Low baseline levels of CRP and leptin, and high baseline levels of TNF-RI and VCAM-1 were associated with LDA after 3 months of MTX therapy in patients with eRA. Combination of these 4 biomarkers increased accuracy of prediction. [Trial registration number: NCT00764725].
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Affiliation(s)
- Karen Hambardzumyan
- From the Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Crescendo Bioscience, South San Francisco, California, USA; Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden; Amsterdam Rheumatology and Immunology Center, Amsterdam, the Netherlands; Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden.,K. Hambardzumyan, MSc, Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital; R.J. Bolce, MSN, Crescendo Bioscience; J.K. Wallman, MD, PhD, Section of Rheumatology, Department of Clinical Sciences Lund, Lund University; R.F. van Vollenhoven, MD, PhD, Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, and Amsterdam Rheumatology and Immunology Center; S. Saevarsdottir, MD, PhD, Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, and Unit of Translational Epidemiology, Institute of Environmental Medicine, Karolinska Institutet
| | - Rebecca J Bolce
- From the Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Crescendo Bioscience, South San Francisco, California, USA; Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden; Amsterdam Rheumatology and Immunology Center, Amsterdam, the Netherlands; Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden.,K. Hambardzumyan, MSc, Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital; R.J. Bolce, MSN, Crescendo Bioscience; J.K. Wallman, MD, PhD, Section of Rheumatology, Department of Clinical Sciences Lund, Lund University; R.F. van Vollenhoven, MD, PhD, Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, and Amsterdam Rheumatology and Immunology Center; S. Saevarsdottir, MD, PhD, Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, and Unit of Translational Epidemiology, Institute of Environmental Medicine, Karolinska Institutet
| | - Johan K Wallman
- From the Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Crescendo Bioscience, South San Francisco, California, USA; Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden; Amsterdam Rheumatology and Immunology Center, Amsterdam, the Netherlands; Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden.,K. Hambardzumyan, MSc, Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital; R.J. Bolce, MSN, Crescendo Bioscience; J.K. Wallman, MD, PhD, Section of Rheumatology, Department of Clinical Sciences Lund, Lund University; R.F. van Vollenhoven, MD, PhD, Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, and Amsterdam Rheumatology and Immunology Center; S. Saevarsdottir, MD, PhD, Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, and Unit of Translational Epidemiology, Institute of Environmental Medicine, Karolinska Institutet
| | - Ronald F van Vollenhoven
- From the Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Crescendo Bioscience, South San Francisco, California, USA; Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden; Amsterdam Rheumatology and Immunology Center, Amsterdam, the Netherlands; Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden.,K. Hambardzumyan, MSc, Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital; R.J. Bolce, MSN, Crescendo Bioscience; J.K. Wallman, MD, PhD, Section of Rheumatology, Department of Clinical Sciences Lund, Lund University; R.F. van Vollenhoven, MD, PhD, Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, and Amsterdam Rheumatology and Immunology Center; S. Saevarsdottir, MD, PhD, Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, and Unit of Translational Epidemiology, Institute of Environmental Medicine, Karolinska Institutet
| | - Saedis Saevarsdottir
- From the Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Crescendo Bioscience, South San Francisco, California, USA; Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden; Amsterdam Rheumatology and Immunology Center, Amsterdam, the Netherlands; Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden. .,K. Hambardzumyan, MSc, Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital; R.J. Bolce, MSN, Crescendo Bioscience; J.K. Wallman, MD, PhD, Section of Rheumatology, Department of Clinical Sciences Lund, Lund University; R.F. van Vollenhoven, MD, PhD, Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, and Amsterdam Rheumatology and Immunology Center; S. Saevarsdottir, MD, PhD, Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, and Unit of Translational Epidemiology, Institute of Environmental Medicine, Karolinska Institutet.
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20
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Dudics S, Langan D, Meka RR, Venkatesha SH, Berman BM, Che CT, Moudgil KD. Natural Products for the Treatment of Autoimmune Arthritis: Their Mechanisms of Action, Targeted Delivery, and Interplay with the Host Microbiome. Int J Mol Sci 2018; 19:E2508. [PMID: 30149545 PMCID: PMC6164747 DOI: 10.3390/ijms19092508] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 08/12/2018] [Accepted: 08/18/2018] [Indexed: 12/16/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic, debilitating illness characterized by painful swelling of the joints, inflammation of the synovial lining of the joints, and damage to cartilage and bone. Several anti-inflammatory and disease-modifying drugs are available for RA therapy. However, the prolonged use of these drugs is associated with severe side effects. Furthermore, these drugs are effective only in a proportion of RA patients. Hence, there is a need to search for new therapeutic agents that are effective yet safe. Interestingly, a variety of herbs and other natural products offer a vast resource for such anti-arthritic agents. We discuss here the basic features of RA pathogenesis; the commonly used animal models of RA; the mainstream drugs used for RA; the use of well-characterized natural products possessing anti-arthritic activity; the application of nanoparticles for efficient delivery of such products; and the interplay between dietary products and the host microbiome for maintenance of health and disease induction. We believe that with several advances in the past decade in the characterization and functional studies of natural products, the stage is set for widespread clinical testing and/or use of these products for the treatment of RA and other diseases.
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Affiliation(s)
- Steven Dudics
- Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | - David Langan
- Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | - Rakeshchandra R Meka
- Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | - Shivaprasad H Venkatesha
- Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | - Brian M Berman
- Family and Community Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
- Center for Integrative Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | - Chun-Tao Che
- Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
| | - Kamal D Moudgil
- Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
- Division of Rheumatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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21
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Methotrexate mechanism in treatment of rheumatoid arthritis. Joint Bone Spine 2018; 86:301-307. [PMID: 30081197 DOI: 10.1016/j.jbspin.2018.07.004] [Citation(s) in RCA: 247] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 07/20/2018] [Indexed: 01/17/2023]
Abstract
Methotrexate has been used in treatment of rheumatoid arthritis (RA) since the 1980s and to this day is often the first line medication for RA treatment. In this review, we examine multiple hypotheses to explain the mechanism of methotrexate efficacy in RA. These include folate antagonism, adenosine signaling, generation of reactive oxygen species (ROS), decrease in adhesion molecules, alteration of cytokine profiles, and polyamine inhibition amongst some others. Currently, adenosine signaling is probably the most widely accepted explanation for the methotrexate mechanism in RA given that methotrexate increases adenosine levels and on engagement of adenosine with its extracellular receptors an intracellular cascade is activated promoting an overall anti-inflammatory state. In addition to these hypotheses, we examine the mechanism of methotrexate in RA from the perspective of its adverse effects and consider some of the newer genetic markers of methotrexate efficacy and toxicity in RA. Lastly, we briefly discuss the mechanism of additive methotrexate in the setting of TNF-α inhibitor treatment of RA. Ultimately, finding a clear explanation for the pathway and mechanism leading to methotrexate efficacy in RA, there may be a way to formulate more potent therapies with fewer side effects.
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22
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Sandhu A, Ahmad S, Kaur P, Bhatnagar A, Dhawan V, Dhir V. Methotrexate preferentially affects Tc1 and Tc17 subset of CD8 T lymphocytes. Clin Rheumatol 2018; 38:37-44. [DOI: 10.1007/s10067-018-4011-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 01/01/2018] [Accepted: 01/29/2018] [Indexed: 01/01/2023]
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Owczarczyk-Saczonek A, Drozdowski M, Maciejewska-Radomska A, Choszcz D, Placek W. The effect of subcutaneous methotrexate on markers of metabolic syndrome in psoriatic patients - preliminary report. Postepy Dermatol Alergol 2018; 35:53-59. [PMID: 29599672 PMCID: PMC5872240 DOI: 10.5114/ada.2017.71358] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 08/05/2016] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Methotrexate (MTX) has anti-proliferative and anti-inflammatory effects in psoriasis. Moreover, low doses can reduce the risk of developing cardiovascular diseases. It turns out that psoriasis and atherosclerosis have a similar pathogenetic mechanism: the same pro-inflammatory cytokines, Th1 and Th17, are involved in both diseases. AIM To evaluate the effects of metabolic markers, protective cytokines (interleukin 10 (IL-10), transforming growth factor β (TGF-β)) and a marker of endothelial damage (endocan) in patients with plaque psoriasis. MATERIAL AND METHODS The study included 24 patients aged 27-69 years (9 female, 15 male) with plaque psoriasis. The metabolic syndrome according to the International Diabetes Federation (IDF) was evaluated. The laboratory tests were performed under fasting conditions: C-reactive protein (CRP), glucose, total cholesterol, triglycerides, high-density lipoprotein (HDL), uric acid, endocan, IL-10, and TGF-β. After 12 weeks of treatment with MTX injections 15 mg/week, every patient was assessed with the same laboratory tests. RESULTS After treatment we observed a statistically significant increase of endocan and IL-10, but no significant differences in the titer of TGF-β. C-reactive protein was reduced by approximately 54.7%. No improvement of lipid profile was observed, and even a significant increase in triglycerides was noted. Similarly, no significant difference was seen in the case of glucose and uric acid prior to and after treatment. CONCLUSIONS Methotrexate in low doses in short-term treatment decreases CRP (anti-inflammatory effect) and increases endocan and IL-10 (potential protective role). Methotrexate is characterized by good efficacy and tolerability in therapy of patients with psoriasis.
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Affiliation(s)
- Agnieszka Owczarczyk-Saczonek
- Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology, University of Warmia and Mazury, Olsztyn, Poland
| | - Marek Drozdowski
- Department of Laboratory Medicine, University of Warmia and Mazury, Olsztyn, Poland
| | - Agata Maciejewska-Radomska
- Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology, University of Warmia and Mazury, Olsztyn, Poland
| | - Dariusz Choszcz
- Department of Machines and Research Methodology, Faculty of Technical Sciences, University of Warmia and Mazury, Olsztyn, Poland
| | - Waldemar Placek
- Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology, University of Warmia and Mazury, Olsztyn, Poland
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Kuuliala K, Kuuliala A, Koivuniemi R, Kautiainen H, Repo H, Leirisalo-Repo M. STAT6 and STAT1 Pathway Activation in Circulating Lymphocytes and Monocytes as Predictor of Treatment Response in Rheumatoid Arthritis. PLoS One 2016; 11:e0167975. [PMID: 27942004 PMCID: PMC5152841 DOI: 10.1371/journal.pone.0167975] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 10/27/2016] [Indexed: 12/29/2022] Open
Abstract
Objective To find novel predictors of treatment response to disease-modifying antirheumatic drugs (DMARDs), we studied activation of STAT (signal transducers and activators of transcription) 6 and 1 in circulating leukocytes of patients with rheumatoid arthritis (RA). Methods 19 patients with untreated recent-onset RA, 16 patients with chronic RA irresponsive to synthetic DMARDs and 37 healthy volunteers provided blood samples for whole blood flow cytometric determination of intracellular STAT6 and STAT1 phosphorylation, expressed as relative fluorescence units, in response to IL-4 and IFN-γ, respectively. Phosphorylation was restudied and treatment response (according to European League Against Rheumatism) determined after 1-year treatment with synthetic DMARDs in recent-onset RA and with biological DMARD in synthetic DMARD-irresponsive RA. Estimation-based exact logistic regression was used to investigate relation of baseline variables to treatment response. 95% confidence intervals of means were estimated by bias-corrected bootstrapping and the significance between baseline and follow-up values was calculated by permutation test. Results At baseline, levels of phosphorylated STAT6 (pSTAT6) induced by IL-4 in monocytes were higher in those who achieved good treatment response to synthetic DMARDs than in those who did not among patients with untreated RA (OR 2.74, 95% CI 1.05 to 9.47), and IFN-γ -stimulated lymphocyte pSTAT1 levels were higher in those who achieved good treatment response to a biological drug than in those who did not among patients with chronic RA (OR 3.91, 95% CI 1.12 to 20.68). During follow-up, in recent-onset RA patients with good treatment response to synthetic DMARDS, the lymphocyte pSTAT6 levels decreased (p = 0.011), and, consequently, the ratio of pSTAT1/pSTAT6 in lymphocytes increased (p = 0.042). Conclusion Cytokine-stimulated STAT6 and STAT1 phosphorylation in circulating leukocytes was associated with treatment response to DMARDs in this pilot study. The result, if confirmed in larger studies, may aid in developing personalized medicine in RA.
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Affiliation(s)
- Krista Kuuliala
- Bacteriology and immunology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- * E-mail:
| | - Antti Kuuliala
- Bacteriology and immunology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Riitta Koivuniemi
- Rheumatology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Hannu Kautiainen
- Primary Health Care, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- General Practice, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- Unit of Primary Health Care, Kuopio University Hospital, Kuopio, Finland
| | - Heikki Repo
- Bacteriology and immunology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers. Nat Rev Rheumatol 2016; 12:731-742. [PMID: 27784891 DOI: 10.1038/nrrheum.2016.175] [Citation(s) in RCA: 277] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The treatment and outcomes of patients with rheumatoid arthritis (RA) have been transformed over the past two decades. Low disease activity and remission are now frequently achieved, and this success is largely the result of the evolution of treatment paradigms and the introduction of new therapeutic agents. Despite the rapid pace of change, the most commonly used drug in RA remains methotrexate, which is considered the anchor drug for this condition. In this Review, we describe the known pharmacokinetic properties and putative mechanisms of action of methotrexate. Consideration of the pharmacodynamic perspective could inform the development of biomarkers of responsiveness to methotrexate, enabling therapy to be targeted to specific groups of patients. Such biomarkers could revolutionize the management of RA.
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Quetglas EG, Mujagic Z, Wigge S, Keszthelyi D, Wachten S, Masclee A, Reinisch W. Update on pathogenesis and predictors of response of therapeutic strategies used in inflammatory bowel disease. World J Gastroenterol 2015; 21:12519-12543. [PMID: 26640330 PMCID: PMC4658608 DOI: 10.3748/wjg.v21.i44.12519] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
The search for biomarkers that characterize specific aspects of inflammatory bowel disease (IBD), has received substantial interest in the past years and is moving forward rapidly with the help of modern technologies. Nevertheless, there is a direct demand to identify adequate biomarkers for predicting and evaluating therapeutic response to different therapies. In this subset, pharmacogenetics deserves more attention as part of the endeavor to provide personalized medicine. The ultimate goal in this area is the adjustment of medication for a patient’s specific genetic background and thereby to improve drug efficacy and safety rates. The aim of the following review is to utilize the latest knowledge on immunopathogenesis of IBD and update the findings on the field of Immunology and Genetics, to evaluate the response to the different therapies. In the present article, more than 400 publications were reviewed but finally 287 included based on design, reproducibility (or expectancy to be reproducible and translationable into humans) or already measured in humans. A few tests have shown clinical applicability. Other, i.e., genetic associations for the different therapies in IBD have not yet shown consistent or robust results. In the close future it is anticipated that this, cellular and genetic material, as well as the determination of biomarkers will be implemented in an integrated molecular diagnostic and prognostic approach to manage IBD patients.
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Singh H, Kumaran MS, Bains A, Parsad D. A Randomized Comparative Study of Oral Corticosteroid Minipulse and Low-Dose Oral Methotrexate in the Treatment of Unstable Vitiligo. Dermatology 2015; 231:286-90. [PMID: 26278124 DOI: 10.1159/000433424] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 05/15/2015] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Despite continued progress towards elucidation of the biochemical, genetic and immunopathological pathways in vitiligo, a definitive cure remains elusive. The initial therapy must be directed to arrest disease progression. Oral minipulse therapy (OMP) with betamethasone/dexamethasone has been tried and shown to be an effective modality to arrest the disease progression in vitiligo. OBJECTIVES Methotrexate (MTX) is a time-tested effective treatment extensively used in various autoimmune disorders with good efficacy, safety and tolerability on a long-term basis. We intended to compare the efficacy of MTX with that of OMP in patients with unstable vitiligo vulgaris. PATIENTS AND METHODS In a prospective randomized open label study, 52 patients with vitiligo were divided into two groups. Patients in group 1 received 10 mg methotrexate weekly. Group 2 patients received corticosteroid OMP which comprised tablets of dexamethasone 2.5 mg (5 tablets), taken on 2 consecutive days in a week (total weekly dose of 5 mg dexamethasone). RESULTS In the MTX group, among 25 patients analyzed, during the course of treatment for 24 weeks, overall 6 patients developed new vitiliginous lesions. In the OMP group, 7/25 patients developed new lesions. Statistical correlation between the two groups showed no significance in the number of patients who developed new lesions (increasing disease activity) in either of the groups. At the end of the study, it was demonstrated that patients in both groups had a similar reduction in the vitiligo disease activity score. CONCLUSION Our study demonstrated that both drugs are equally effective in controlling the disease activity of vitiligo. MTX can be used in patients with active vitiligo, wherever corticosteroids are contraindicated.
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Affiliation(s)
- Harsimer Singh
- Department of Dermatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Spurlock CF, Gass HM, Bryant CJ, Wells BC, Olsen NJ, Aune TM. Methotrexate-mediated inhibition of nuclear factor κB activation by distinct pathways in T cells and fibroblast-like synoviocytes. Rheumatology (Oxford) 2015; 54:178-87. [PMID: 25118313 PMCID: PMC4269792 DOI: 10.1093/rheumatology/keu279] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 05/22/2014] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES Nuclear factor κB (NF-κB) is a critical activator of inflammatory processes and MTX is one of the most commonly prescribed DMARDs for treatment of RA. We sought to determine whether MTX inhibited NF-κB activity in RA and in lymphocytes and fibroblast-like synoviocytes (FLSs) and to define underlying mechanisms of action. METHODS An NF-κB luciferase reporter plasmid was used to measure NF-κB activation across experimental stimuli. Flow cytometry was used to quantify changes in intracellular protein levels, measure levels of reactive oxygen species and determine apoptosis. Quantitative RT-PCR was used to identify changes in MTX target genes. RESULTS In T cell lines, MTX (0.1 μM) inhibited activation of NF-κB via depletion of tetrahydrobiopterin (BH4) and increased Jun-N-terminal kinase (JNK)-dependent p53 activity. Inhibitors of BH4 activity or synthesis also inhibited NF-κB activation and, similar to MTX, increased JNK, p53, p21 and JUN activity. Patients with RA expressed increased levels of phosphorylated or active RelA (p65) compared with controls. Levels of phosphorylated RelA were reduced in patients receiving low-dose MTX therapy. In contrast, inhibition of NF-κB activation by MTX was not mediated via BH4 depletion and JNK activation in FLSs, but rather was completely prevented by adenosine receptor antagonists. CONCLUSION Our findings support a model whereby distinct pathways are activated by MTX in T cells and FLSs to inhibit NF-κB activation.
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Affiliation(s)
- Charles F Spurlock
- Department of Pathology, Microbiology and Immunology, Department of Medicine, Center for Science Outreach, Vanderbilt University, Nashville, TN and Division of Rheumatology, Department of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Henry M Gass
- Department of Pathology, Microbiology and Immunology, Department of Medicine, Center for Science Outreach, Vanderbilt University, Nashville, TN and Division of Rheumatology, Department of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Carson J Bryant
- Department of Pathology, Microbiology and Immunology, Department of Medicine, Center for Science Outreach, Vanderbilt University, Nashville, TN and Division of Rheumatology, Department of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Benjamin C Wells
- Department of Pathology, Microbiology and Immunology, Department of Medicine, Center for Science Outreach, Vanderbilt University, Nashville, TN and Division of Rheumatology, Department of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Nancy J Olsen
- Department of Pathology, Microbiology and Immunology, Department of Medicine, Center for Science Outreach, Vanderbilt University, Nashville, TN and Division of Rheumatology, Department of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Thomas M Aune
- Department of Pathology, Microbiology and Immunology, Department of Medicine, Center for Science Outreach, Vanderbilt University, Nashville, TN and Division of Rheumatology, Department of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA. Department of Pathology, Microbiology and Immunology, Department of Medicine, Center for Science Outreach, Vanderbilt University, Nashville, TN and Division of Rheumatology, Department of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.
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Rizzo R, Bortolotti D, Bolzani S, Fainardi E. HLA-G Molecules in Autoimmune Diseases and Infections. Front Immunol 2014; 5:592. [PMID: 25477881 PMCID: PMC4235267 DOI: 10.3389/fimmu.2014.00592] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 11/04/2014] [Indexed: 01/22/2023] Open
Abstract
Human leukocyte antigen (HLA)-G molecule, a non-classical HLA-Ib molecule, is less polymorphic when compared to classical HLA class I molecules. Human leukocyte antigen-G (HLA-G) was first detected on cytotrophoblast cells at the feto-maternal interface but its expression is prevalent during viral infections and several autoimmune diseases. HLA-G gene is characterized by polymorphisms at the 3' un-translated region and 5' upstream regulatory region that regulate its expression and are associated with autoimmune diseases and viral infection susceptibility, creating an unbalanced and pathologic environment. This review focuses on the role of HLA-G genetic polymorphisms, mRNA, and protein expression in autoimmune conditions and viral infections.
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Affiliation(s)
- Roberta Rizzo
- Section of Microbiology and Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Daria Bortolotti
- Section of Microbiology and Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Silvia Bolzani
- Section of Microbiology and Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Enrico Fainardi
- Neuroradiology Unit, Department of Neurosciences and Rehabilitation, Azienda Ospedaliera-Universitaria Arcispedale S. Anna, Ferrara, Italy
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Cipriani P, Ruscitti P, Carubbi F, Liakouli V, Giacomelli R. Methotrexate: an old new drug in autoimmune disease. Expert Rev Clin Immunol 2014; 10:1519-30. [PMID: 25245537 DOI: 10.1586/1744666x.2014.962996] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Methotrexate (MTX) is currently considered, among disease-modifying anti-rheumatic drugs (DMARDs), the 'anchor-drug' in the treatment of rheumatoid arthritis. In the last 25 years, there has been a marked expansion in the use of MTX in different inflammatory diseases. Its low cost, associated to a good long-term efficacy and safety profile, justifies the use of MTX as a first-line disease-modifying drug or alternatively, a steroid-sparing medication in this field of medicine. Although new emerging options, including biological treatments, are being established in the therapeutic scenario, the good cost/benefit ratio of MTX supports the choice of this drug in combination with these newer therapies, enhancing the efficacy of these combination therapies and decreasing the risk of potential side effects.
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Affiliation(s)
- Paola Cipriani
- Department of Biotechnological and Applied Clinical Science, Rheumatology Unit, School of Medicine, University of L'Aquila, Delta 6 Building, Via dell'Ospedale, 67100, L'Aquila, Italy
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Alghamdi K, Khurrum H. Methotrexate for the treatment of generalized vitiligo. Saudi Pharm J 2013; 21:423-4. [PMID: 24227963 DOI: 10.1016/j.jsps.2012.12.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 12/08/2012] [Indexed: 11/27/2022] Open
Affiliation(s)
- Khalid Alghamdi
- Dermatology Department, Vitiligo Research Chair, College of Medicine, King Saud University, P.O. Box 240997, Riyadh 11322, Saudi Arabia ; Vitiligo Research Chair, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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Bordon JM, Uriarte S, Arnold FW, Fernandez-Botran R, Rane M, Peyrani P, Cavallazzi R, Saad M, Ramirez J. Cytokines and neutrophils responses in influenza pneumonia. Infection 2013; 41:1021-4. [PMID: 23589279 DOI: 10.1007/s15010-013-0461-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2013] [Accepted: 04/04/2013] [Indexed: 01/26/2023]
Abstract
This case report shows a striking correlation of remarkable brief high levels of pro- and anti-inflammatory cytokines coupled with increased neutrophil activation, followed by a sharp decrease in cytokine levels and increased neutrophil apoptosis associated with the favorable clinical outcomes of a patient with severe influenza infection. The host response examined in our case is not complete, given it did not assess the full spectrum of host response. The brief neutrophil and cytokine response seen in our case in the absence of antiviral therapy and in the presence of methotrexate immunosuppressive therapy rise the question as to whether the latter optimally modulated the macrophage function, resulting in a favorable outcome of severe influenza viral infection.
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Affiliation(s)
- J M Bordon
- Section of Infectious Diseases, Providence Hospital, 1150 Varnum Street, NE, Washington, DC, 20017, USA,
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Ćalasan MB, Thurlings RM, Wulffraat NM, Prakken BJ. Translational medicine from bedside to bench and back again: methotrexate revisited. ACTA ACUST UNITED AC 2013. [DOI: 10.2217/ijr.13.13] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Romão VC, Canhão H, Fonseca JE. Old drugs, old problems: where do we stand in prediction of rheumatoid arthritis responsiveness to methotrexate and other synthetic DMARDs? BMC Med 2013; 11:17. [PMID: 23343013 PMCID: PMC3606422 DOI: 10.1186/1741-7015-11-17] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2012] [Accepted: 01/23/2013] [Indexed: 02/08/2023] Open
Abstract
Methotrexate (MTX) is the central drug in the management of rheumatoid arthritis (RA) and other immune mediated inflammatory diseases. It is widely used either in monotherapy or in association with other synthetic and biologic disease modifying anti-rheumatic drugs (DMARDs). Although comprehensive clinical experience exists for MTX and synthetic DMARDs, to date it has not been possible to preview correctly whether or not a patient will respond to treatment with these drugs. Predicting response to MTX and other DMARDs would allow the selection of patients based on their likelihood of response, thus enabling individualized therapy and avoiding unnecessary adverse effects and elevated costs. However, studies analyzing this issue have struggled to obtain consistent, replicable results and no factor has yet been recognized to individually distinguish responders from nonresponders at treatment start. Variables possibly influencing drug effectiveness may be disease-, patient- or treatment-related, clinical or biological (genetic and nongenetic). In this review we summarize current evidence on predictors of response to MTX and other synthetic DMARDs, discuss possible causes for the heterogeneity observed and address its translation into daily clinical practice.
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Affiliation(s)
- Vasco Crispim Romão
- Rheumatology Research Unit, Instituto de Medicina Molecular - Faculdade de Medicina da Universidade de Lisboa, Edifício Egas Moniz - Av, Prof, Egas Moniz, Lisboa 1649-028, Portugal
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Chen Z, Tu S, Hu Y, Wang Y, Xia Y, Jiang Y. Prediction of response of collagen-induced arthritis rats to methotrexate: An 1H-NMR-based urine metabolomic analysis. ACTA ACUST UNITED AC 2012; 32:438-443. [DOI: 10.1007/s11596-012-0076-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Indexed: 12/25/2022]
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Wang Z, Chen Z, Yang S, Wang Y, Yu L, Zhang B, Rao Z, Gao J, Tu S. (1)H NMR-based metabolomic analysis for identifying serum biomarkers to evaluate methotrexate treatment in patients with early rheumatoid arthritis. Exp Ther Med 2012; 4:165-171. [PMID: 23060942 DOI: 10.3892/etm.2012.567] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Accepted: 04/20/2012] [Indexed: 01/16/2023] Open
Abstract
To identify the major serum biomarkers predicting the response to methotrexate (MTX) treatment in patients with early rheumatoid arthritis (RA), we evaluated the relationships between the individual response to MTX and various associated factors utilizing the (1)H nuclear magnetic resonance ((1)H NMR)-based metabolomic method. Thirty-eight early RA patients were enrolled in this cohort study, and they received MTX (10 mg/week) orally as monotherapy for 24 weeks. According to the American College of Rheumatology criteria for improvement, clinical evaluation following MTX treatment was carried out at baseline and at the end of 24 weeks. Furthermore, collected serum samples were analyzed using 600 M (1)H NMR for spectral binning. The obtained data were processed by both the unsupervised principal component analysis (PCA) and the supervised partial least squares discriminant analysis (PLS-DA). Lastly, multivariate analyses were performed to recognize the spectral pattern of endogenous metabolites related to MTX treatment. Differential clustering of (1)H NMR spectra identified by PCA was found between the effective (n=25) and non-effective (n=13) group of RA patients receiving MTX treatment. Multivariate statistical analysis showed a difference in metabolic profiles between the two groups using PLS-DA (R(2)=0.802, Q(2)=0.643). In targeted profiling, 11 endogenous metabolites of the effective group showed a significant difference when compared with those of the non-effective group (p<0.05). Serum metabolites correlated with MTX treatment in patients with early RA were identified, which may be the major predictive factors for evaluating the response to MTX treatment in patients with early RA. Furthermore, our results highlight the usefulness of (1)H NMR-based metabolomics as a feasible and efficient prognostic tool for predicting therapeutic efficacy to MTX treatment.
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Affiliation(s)
- Zhigang Wang
- Department of Oncology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army, Wuhan 430070
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Ulusoy H, Kamanli A, Ilhan N, Kuru O, Arslan S, Alkan G, Ozgocmen S. Serum levels of soluble CD26 and CD30 and their clinical significance in patients with rheumatoid arthritis. Rheumatol Int 2011; 32:3857-62. [PMID: 22193227 DOI: 10.1007/s00296-011-2302-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2011] [Accepted: 12/10/2011] [Indexed: 11/28/2022]
Abstract
The aim of this study was to assess serum levels and clinical significance of soluble CD26 (sCD26) and soluble CD30 (sCD30) in patients with rheumatoid arthritis (RA). Forty-eight patients with RA and 30 healthy controls were enrolled. Serum sCD26 and sCD30 levels were measured using ELISA. Serum sCD26 levels were significantly lower (P = 0.011), whereas sCD30 levels were higher (P = 0.008) in patients with RA than controls. Serum levels of sCD30 correlated significantly with clinical and laboratory parameters of disease activity like erythrocyte sedimentation rate, C-reactive protein, disease activity scores-28 and health assessment questionnaire score; however, sCD26 levels did not correlate any of these activity parameters. These results suggest that serum sCD30 levels increased and correlated significantly with disease activity, indicating a novel follow-up parameter in RA. Serum levels of sCD26 may be lessen but not related to disease activity in RA.
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Affiliation(s)
- Hasan Ulusoy
- Division of Rheumatology, Department of Physical Medicine and Rehabilitation, Firat University, Faculty of Medicine, Elazig, Turkey.
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Prediction of response to disease modifying antirheumatic drugs in rheumatoid arthritis. Joint Bone Spine 2010; 77:558-63. [PMID: 20478729 DOI: 10.1016/j.jbspin.2010.02.018] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2009] [Accepted: 02/24/2010] [Indexed: 01/06/2023]
Abstract
AIM To investigate potential predictors of response to conventional DMARDs in RA. METHODS Study design - 6-month follow-up prospective study. PARTICIPANTS RA patients with active disease. INTERVENTION AND FOLLOW-UP: Introduction of one DMARD. Response to treatment evaluated at 6 months (ACR20 criteria). ANALYSIS Potential predictors of response, patients' demographics, disease activity, percentages of PBMC subsets expressing P-gp, serum IL-1β, IL-6, IL-8, IL-10, IL-12, TNF-α levels, were evaluated using univariate and multivariate logistic regression analysis. ROC curve analyses were performed in order to obtain thresholds allowing the prediction of response. RESULTS Forty-two patients (mean age = 57 ± 13 years, mean disease duration = 5.4 ± 7.2 years) were included. MTX was given to 30. The response to therapy was predicted by the baseline serum level of TNF-α (mean = 30.2 pg/ml ± 18 in non-responders vs. 11.9 pg/ml ± 11.2 in responders). The threshold, which predicted with the best accuracy the response to treatment, was 20.1 pg/ml (sensitivity, specificity, positive and negative predictive values of 75, 78.9, 83.3, and 69.2%, respectively; AUC = 80.3%, 95% CI = 62.8-97.7%). Similar results were obtained in the subgroups of patients treated with MTX and patients with early RA of less than 3 years duration. CONCLUSION In the present work, the serum concentration of TNF-α was related to further response to DMARDs. Other works are needed for confirmation and to assess whether such biomarker could be used to predict the response to DMARDs at the individual level.
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Kooloos WM, Wessels JA, van der Straaten T, Allaart CF, Huizinga TW, Guchelaar HJ. Functional polymorphisms and methotrexate treatment outcome in recent-onset rheumatoid arthritis. Pharmacogenomics 2010; 11:163-75. [PMID: 20136356 DOI: 10.2217/pgs.09.139] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
AIMS Clinical response to methotrexate (MTX) treatment differs among rheumatoid arthritis patients. Genetic variation can partly account for this phenomenon. In this study, functional polymorphisms in genes related to the mechanism of action of MTX or immunopathogenesis of rheumatoid arthritis were studied for association with treatment outcome in a Dutch cohort of patients with early rheumatoid arthritis. Furthermore, tests for replication of previous research on these genetic variants were performed according to reported end points. MATERIALS & METHODS Seven polymorphisms in seven genes were analyzed in 205 genotyped patients with active rheumatoid arthritis. All patients received standardized MTX treatment (< or =25 mg per week orally) combined with folic acid. MTX treatment outcome was evaluated by disease activity score criteria and adverse drug events. The following genetic variants were analyzed and correlated: ABCB1 3435C>T, ITPA IVS2 +21A>C, HLA-G (-14 bp >+14 bp), TGFB1 +869T>C and TLR4 +896A>G. In case of significant differences, regression analyses were applied. Since carriers of the minor alleles of the SNPs DHFR 829C>T and IMPDH2 +787C>T were not observed, no statistical analyses could be performed. RESULTS No significant associations or replications of these genetic variants with MTX efficacy were demonstrated. Regarding toxicity, patients carrying the ABCB1 3435T-allele and TLR4 +896G-allele were 2.5-times more likely to develop adverse drug events at 6 months (odds ratio: 2.6; 95% CI: 1.1-6.2, and odds ratio: 2.5; 95% CI: 1.1-6.1, respectively). Additionally, this chance increased almost fourfold in patients with the two unfavorable genotypes (odds ratio: 3.9; 95% CI: 1.5-10.3). However, none of these associations remained significant after correction for multiple testing (p < 0.004). CONCLUSION Our data indicate that MTX toxicity was potentially associated with ABCB1 3435C>T and TLR4 +896A>G. However, after correction, none of these associations remained significant. Furthermore, no significant associations or replications of these functional variants with efficacy were found.
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Affiliation(s)
- Wouter M Kooloos
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, PO Box 9600, NL 2300 RC Leiden, The Netherlands
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Herman S, Zurgil N, Langevitz P, Ehrenfeld M, Deutsch M. The Immunosuppressive Effect of Methotrexate in Active Rheumatoid Arthritis Patients vs. its Stimulatory Effect in Nonactive Patients, as Indicated by Cytometric Measurements of CD4 + T Cell Subpopulations. Immunol Invest 2009; 33:351-62. [PMID: 15495793 DOI: 10.1081/imm-120039865] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
This cytometric study assesses the effects of methotrexate (MTX) on the expanded CD4+ lymphocyte population in active and nonactive rheumatoid arthritis (RA) patients. In the active patients, MTX was found to reduce the predominant CD4+ CD28+ subpopulation (by 30%), and the minor subpopulation of CD4+ CD28- (by 34%). The incidence of CD25 phenotype was downregulated by 15%. These reductions can be attributed to immunosuppression through apoptosis, which was demonstrated by MTX-induced fluorescein diacetate (FDA) hyperpolarization (an established indicator of early apoptosis). In contrast, in nonactive RA patients, the major CD4+ CD28+ subpopulation of small lymphocytes appeared to be activated by MTX, subsequently transforming into a major hyperblast population, whereas the minor CD4+ CD28- subpopulation was not affected by MTX treatment. The activation by MTX in this group of patients is evidenced by MTX-induced FDA depolarization (an indicator of early activation). Thus, MTX immunosuppressive effect on CD4+ subsets was found in active patients, whereas immunostimulation by MTX was shown in nonactive patients. The found discriminative effect of MTX may suggest a higher effectiveness of low-dose MTX therapy in active RA patients.
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Affiliation(s)
- Shoshy Herman
- Physics Department, The Biophysical Interdisciplinary Jerome Schottenstein Center for the Research and the Technology of the Cellome, Bar-Ilan University, Ramat-Gan, Israel
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Ranganathan P. An update on methotrexate pharmacogenetics in rheumatoid arthritis. Pharmacogenomics 2008; 9:439-51. [PMID: 18384257 DOI: 10.2217/14622416.9.4.439] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Rheumatoid arthritis (RA) is a systemic inflammatory disorder that mainly affects the joints. When left untreated, the disease can result in irreversible joint damage with high morbidity and mortality. Disease-modifying antirheumatic drugs are the cornerstones of treatment in RA. Disease-modifying antirheumatic drugs not only ameliorate the clinical signs and symptoms of disease, but also prevent the radiographic progression of joint damage. Methotrexate is one such disease-modifying antirheumatic drug that has been used in the treatment of RA for over two decades with excellent long-term efficacy and safety. However, there is significant variability in patients' response to methotrexate, both in terms of efficacy and toxicity. At the present time, there are no reliable means of predicting, a priori, an individual patient's response to methotrexate. In this review, recent published literature on the pharmacogenetics of methotrexate in RA is highlighted. Pharmacogenetics may be a powerful tool for optimizing methotrexate therapy in patients with RA.
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Affiliation(s)
- Prabha Ranganathan
- Department of Medicine, Division of Rheumatology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8045, St. Louis, MO 63110, USA.
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Backonja MM, Coe CL, Muller DA, Schell K. Altered cytokine levels in the blood and cerebrospinal fluid of chronic pain patients. J Neuroimmunol 2008; 195:157-63. [PMID: 18325600 DOI: 10.1016/j.jneuroim.2008.01.005] [Citation(s) in RCA: 106] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2007] [Revised: 01/03/2008] [Accepted: 01/16/2008] [Indexed: 12/25/2022]
Abstract
This study replicates and extends prior reports of abnormal cytokine levels in chronic pain patients and has correlated the alterations with pain severity. In addition, there appeared to be a need to directly assess cerebrospinal fluid (CSF) because previous findings on cytokine concentrations in peripheral circulation have been inconsistent. CSF and blood specimens were obtained from 14 patients with distal painful non-diabetic polyneuropathy (DPPN) or post-traumatic neuralgia (PTN). Elevated receptor levels for Tumor Necrosis Factor (sTNFr) were the most distinctive abnormality along with low interleukin-10 (IL-10). sTNFr in CSF and blood, and IL-1ss in CSF, were positively associated with pain intensity, whereas IL-10 in both compartments was inversely correlated with pain symptoms. An imbalance of pro- and anti-inflammatory cytokines appears to be a clinically relevant feature, which may contribute to the maintenance of chronic pain.
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Affiliation(s)
- Miroslav Misha Backonja
- Department of Neurology, Clinical Science Center, University of Wisconsin, Madison 53792, United States.
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Abstract
This article examines the therapeutic potential of methotrexate (MTX) in the treatment of cholestatic liver disease, with specific reference to its use in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). In PBC patients, evidence suggests that a particular subset of patients may benefit, either biochemically or symptomatically, from the addition of MTX to their therapeutic regimen. How best to define these potential MTX responders remains unclear, but may warrant a "therapeutic trial" in some patients with more aggressive disease or in patients with refractory and disabling PBC-related symptoms. In contrast, PSC continues to be an immensely challenging disease to effectively treat, and the role of MTX for treating PSC patients remains dubious.
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Affiliation(s)
- Kerri Novak
- Division of Gastroenterology, Liver Unit, University of Calgary, 3330 Hospital Dr., NW, Health Sciences Center, Calgary, Alberta, Canada T2N 4N1
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Rizzo R, Rubini M, Govoni M, Padovan M, Melchiorri L, Stignani M, Carturan S, Ferretti S, Trotta F, Baricordi OR. HLA-G 14-bp polymorphism regulates the methotrexate response in rheumatoid arthritis. Pharmacogenet Genomics 2006; 16:615-23. [PMID: 16906016 DOI: 10.1097/01.fpc.0000230115.41828.3a] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Methotrexate (MTX) represents the antirheumatic drug mainly used in rheumatoid arthritis (RA). HLA-G antigens are inducible nonclassical major histocompatibility complex class Ib molecules important for maintaining anti-inflammatory conditions. The HLA-G gene is characterized by a deletion/insertion polymorphism of 14 bp that controls specific mRNA stability and protein levels. It has been reported that MTX therapy mediates an increase of interleukin-10-producing cells. This cytokine up-regulates HLA-G expression. For this, we tested the hypothesis of an MTX-mediated HLA-G production and the possible relationship with the HLA-G 14-bp polymorphism. METHODS Peripheral blood mononuclear cells from healthy individuals and non-MTX-treated RA patients were activated with different MTX concentrations, and soluble HLA-G (sHLA-G) and interleukin-10 production was investigated by specific immunoenzymatic assay. HLA-G 14-bp polymorphism genotyping was performed in healthy individuals and RA patients, defined as 'responders' and 'nonresponders' to the MTX therapy. RESULTS MTX activation induces the production of sHLA-G molecules. A significant association was observed between the highest sHLA-G1 concentrations and the -14/-14 bp genotype. The analysis of the HLA-G 14-bp polymorphism in MTX-treated RA patients has confirmed an increase of the -14/-14 bp genotype in the responder group (chi=6.12, P=0.02; chi test) (odds ratio=2.46 (95% confidence interval, 1.26-4.84) P=0.009; logistic regression model). CONCLUSION Our results propose that the MTX induces the production of the anti-inflammatory sHLA-G molecules that concur with the therapy response. Furthermore, the association between -14/-14 bp genotype and MTX clinical outcome proposes this polymorphism as a therapy marker in the early phases of the disease.
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Affiliation(s)
- Roberta Rizzo
- Section of Medical Genetics, Department of Experimental and Diagnostic Medicine University of Ferrara, Ferrara, Italy
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van Dieren JM, Kuipers EJ, Samsom JN, Nieuwenhuis EE, van der Woude CJ. Revisiting the immunomodulators tacrolimus, methotrexate, and mycophenolate mofetil: their mechanisms of action and role in the treatment of IBD. Inflamm Bowel Dis 2006; 12:311-27. [PMID: 16633053 DOI: 10.1097/01.mib.0000209787.19952.53] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Inflammatory bowel diseases (IBDs) are thought to result from unopposed immune responses to normal gut flora in a genetically susceptible host. A variety of immunomodulating therapies are applied for the treatment of patients with IBDs. The first-line treatment for IBDs consists of 5-aminosalicylate and/or budesonide. However, these first-line therapies are often not suitable for continuous treatment or do not suffice for the treatment of severe IBD. Recently, efforts have been made to generate novel selective drugs that are more effective and have fewer side effects. Despite promising results, most of these novel drugs are still in a developmental stage and unavailable for clinical application. Yet, another class of established immunomodulators exists that is successful in the treatment of inflammatory bowel diseases. While waiting for emerging novel therapies, the use of these more established drugs should be considered. Furthermore, one of the advantages of using established immunomodulators is the well-documented knowledge on the long-term side effects and on the mechanisms of action. In this review, the authors discuss 3 well-known immunomodulators that are being applied with increased frequency for the treatment of IBD: tacrolimus, methotrexate, and mycophenolate mofetil. These agents have been used for many years as treatment modalities for immunosuppression after organ transplantation, for the treatment of cancer, and for immunomodulation in several other immune-mediated diseases. First, this review discusses the potential targets for immunomodulating therapies in IBDs. Second, the immunomodulating mechanisms and effects of the 3 immunomodulators are discussed in relationship to these treatment targets.
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Affiliation(s)
- Jolanda M van Dieren
- Department of Gastroenterology and Hepatology, Division of Gastroenterology and Nutrition, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
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Havemose-Poulsen A, Sørensen LK, Stoltze K, Bendtzen K, Holmstrup P. Cytokine profiles in peripheral blood and whole blood cell cultures associated with aggressive periodontitis, juvenile idiopathic arthritis, and rheumatoid arthritis. J Periodontol 2006; 76:2276-85. [PMID: 16332240 DOI: 10.1902/jop.2005.76.12.2276] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Cytokines play a key role in the pathogenesis of inflammatory diseases. An obvious question is whether patients with aggressive periodontitis, juvenile idiopathic arthritis, or rheumatoid arthritis share blood cytokine profiles distinguishing them from individuals free of disease. METHODS The study population consisted of Danish white adults, <35 years of age, diagnosed with localized aggressive periodontitis (LAgP; N = 18), generalized aggressive periodontitis (GAgP; N = 27), juvenile idiopathic arthritis (JIA; N = 10), or rheumatoid arthritis (RA; N = 23) and healthy individuals with no systemic or oral diseases (control [CTRL]; N = 25). Enzyme-linked immunosorbent assays were used to determine the levels of interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-6, IL-10, tumor necrosis factor (TNF)-alpha, and lymphotoxin (LT)-alpha in peripheral blood (plasma) and unstimulated and stimulated whole blood cell cultures from the same blood collection. Autoantibodies (aAb) to IL-1alpha and IL-6 were quantitated by radioimmunoassay. RESULTS Similar patterns of slightly higher IL-10 levels in plasma were found for GAgP and RA patients and in unstimulated cultures for GAgP, RA, and JIA patients. Interestingly, unstimulated cultures also demonstrated similar patterns of higher TNF-alpha levels for these three groups of patients. Similar group patterns of periodontitis patients (LAgP and GAgP) included increased IL-1Ra levels in stimulated cultures, which also showed similar group patterns of arthritis patients (JIA and RA) with respect to higher IL-1alpha and lower LT-alpha levels. Low titers of aAb to IL-1alpha and IL-6 were found in almost all individuals. CONCLUSION Patients with aggressive periodontitis and types of arthritis presented with similar components of blood cytokine profiles distinguishing them from individuals free of disease.
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Affiliation(s)
- Anne Havemose-Poulsen
- Department of Periodontology, School of Dentistry, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
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Ranganathan P, McLeod HL. Methotrexate pharmacogenetics: The first step toward individualized therapy in rheumatoid arthritis. ACTA ACUST UNITED AC 2006; 54:1366-77. [PMID: 16645965 DOI: 10.1002/art.21762] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- Prabha Ranganathan
- Division of Rheumatology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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Detection of human P2X7 nucleotide receptor polymorphisms by a novel monocyte pore assay predictive of alterations in lipopolysaccharide-induced cytokine production. THE JOURNAL OF IMMUNOLOGY 2005; 174:4424-31. [PMID: 15778408 DOI: 10.4049/jimmunol.174.7.4424] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The nucleotide receptor P2X(7) is expressed by most leukocytes and initiates signaling events that amplify numerous LPS responses. We tested the hypothesis that loss-of-function polymorphisms in the human P2X(7) gene predispose to the production of an anti-inflammatory mediator balance. Accordingly, we developed a novel P2X(7) pore assay in whole blood that magnifies the activity from wild-type alleles and preserves the gene dosage effect for the 1513 C polymorphism (AA, 69 +/- 4; AC, 42 +/- 4; and CC, 6 +/- 1-fold stimulation). Thirty of 200 healthy individuals were identified as having low P2X(7) pore activity. Seven low pore subjects were 1513 CC, 3 and 11 participants had the other known variants 946 GA and 1729 TA respectively; the remaining 9 volunteers likely have novel polymorphisms. Because platelets are a large source of extracellular ATP during inflammation, whole blood was treated ex vivo with Salmonella typhimurium LPS in the absence of exogenous nucleotides. LPS-stimulated whole blood from individuals in the low pore activity group generated reduced plasma levels of TNF-alpha (p = 0.036) and higher amounts of IL-10 (p < 0.001) relative to the high pore controls. This reduction in the TNF-alpha to IL-10 ratio persisted to at least 24 h and is further decreased by cotreatment with 2-methylthio-ATP. The ability of P2X(7) polymorphisms to regulate the LPS-induced TNF-alpha to IL-10 ratio suggests that 15% of healthy adults may exhibit anti-inflammatory mediator responses during major infectious perturbations of the immune system, which can be predicted by P2X(7) pore activity.
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Toubi E, Kessel A, Mahmudov Z, Hallas K, Rozenbaum M, Rosner I. Increased Spontaneous Apoptosis of CD4+CD25+T Cells in Patients with Active Rheumatoid Arthritis Is Reduced by Infliximab. Ann N Y Acad Sci 2005; 1051:506-14. [PMID: 16126991 DOI: 10.1196/annals.1361.095] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Increased secretion of tumor necrosis factor-alpha (TNF-alpha), along with interleukin-1 (IL-1) and interleukin-6 (IL-6), is important in the pathogenesis of rheumatoid arthritis (RA). T regulatory CD4(+)CD25(+) cells play a role in maintaining self-tolerance by downregulating Th1-induced proinflammation. This function has been found to be altered in active RA, whereas anti-TNF-alpha therapy has been found to improve the suppressive abilities of these cells. Our objectives were to investigate whether T regulatory cells in patients with active RA display a higher sensitivity to spontaneous apoptosis than in normals, and to look into the potential of infliximab (anti-TNF-alpha therapy) to reduce the sensitivity of these cells to spontaneous apoptosis. Seventeen patients suffering from active RA, having failed multiple disease-modifying antirheumatic drug (DMARD) therapies, were treated with infliximab. Spontaneous apoptosis (as detected by annexin V binding) was determined in all patients and compared with a group of normal individuals at baseline and after three months on infliximab treatment. Peripheral blood mononuclear cells were incubated in 24-well plates at 1 x 10(6) cells/mL for 48 hours. Annexin V binding on CD4(+)CD25(+) was assessed using three-color assay by flow cytometry. Prior to infliximab initiation, spontaneous apoptosis of T regulatory cells from active RA patients was found to be increased in comparison with controls (26 +/- 4.2% vs. 19.8 +/- 4.8%, respectively; P = 0.01). Three months later (while still on infliximab) spontaneous apoptosis was comparable in the two groups (20.7 +/- 5.2% vs. 20.9 +/- 3.4%; P 5 0.8). The absolute number of CD4(+)CD25(+) cells/mL in the peripheral blood at baseline was reduced in 11 out of 17 active RA patients when compared with that of the control group (24 +/- 7 vs. 32 +/- 11, respectively; P = 0.02). Following anti-TNF-alpha therapy, CD4(+)CD25(+) cell counts of patients were equivalent to those of normals. The alteration and reversal in both spontaneous apoptosis and cell count of T regulatory cells was found to correlate with RA disease activity. CD4(+)CD25(+) T regulatory cells display increased proclivity to undergo spontaneous apoptosis in active RA. Alterations in CD4(+)CD25(+) cell apoptosis and cell count were found to correlate with RA disease activity. Reversal of these deviations from normal was documented in association with the beneficial outcome of infliximab therapy.
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Affiliation(s)
- E Toubi
- Division of Allergy and Clinical Immunology, Bnai-Zion Medical Center, Golomb Str. 47, P. O. Box 4, Haifa, Israel.
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